Parkinson's disease (PD) was long considered the archetypal non-genetic disease entity. A combination of increased understanding of complex genetics and the use of isolated populations has clarified that genetics plays a significant role in the risk of PD. We are assessing the role of genetics in PD usign two approaches, firstly a case-control association study and secondly a mutation screening approach. Using well characterized patient and control cohorts from Finland we are utilizing a case control methodology to elucidate the role of candidate loci in PD. Consideration of genetic loci for assessment is based on prior association, gene function or genetic localization. Genetic variation such as single nucleotide polymorphisms and simple tandem repeats will be initially identified in genes of interest by web-based data mining techniques with the assistance of the bioinformatics core of LNG. Although non-functional variation is useful for constructing haplotypes across genes we will initially prioritise variation by functional relevance. To maximise the likelihood of identifying functional variation regions of high conservation across mammalian species will be initially targeted, with emphasis on promoter regions. To date we have assessed varation within the genes encoding inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), alpha-synuclein, GTP cyclohydrolase, parkin, Tau, APO E, DJ-1, UCH-L1, FRM1, SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, DRPLA and NAT2. Results identifying a consistent protective effect against PD of variation within the iNOS gene is currently in press at neurology. Likewise the first assessment of the DJ-1 gene as a risk factor for typical PD is also in press. In the previous 4 years we have collected a large series of patients with a strong family history of PD. We assess these cases for mutations within genes associated with parkinsonism, including the SCA genes, alpha-synuclein, DJ-1, parkin and GTP-cyclohydrolase. These genes are assessed by a combination of direct sequencing and semi-quantitative real-time PCR amplification. We have shown that mutations in DJ-1 are a rare (<1%) cause of young-onset PD and that disease caused by mutation at this locus can present without family history. In 2003 we identified a triplication of the alpha-synuclein gene as a cause of PD in a large well-characterized family with autosomal dominant disease. THis work provided the first mechanistic link between alpha-synuclein and Parkinson's disease. Recently we have been led a project which aimed to assess the incidence of PINK1 mutations in Parkinson;s disease and have published data which suggests these mutations are a rare cause of young onset disease.